Journal
JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM
Volume 29, Issue 10, Pages 1644-1654Publisher
SAGE PUBLICATIONS INC
DOI: 10.1038/jcbfm.2009.83
Keywords
doublecortin; ischemia; Jagged1; neurogenesis; Notch1; subventricular zone
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Funding
- NIA NIH HHS [R01 AG021980, R01 AG021980-05, AG21980] Funding Source: Medline
- NINDS NIH HHS [NS44921, R01 NS044921] Funding Source: Medline
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The Notch1 signaling pathway is regarded as one of the main regulators of neural stem cell behavior during development, but its role in the adult brain is less well understood. We found that Notch1 was mainly expressed in doublecortin (DCX)-positive cells corresponding to newborn neurons, whereas the Notch1 ligand, Jagged1, was predominantly expressed in glial fibrillary acidic protein (GFAP)-positive astrocytic cells in the subventricular zone (SVZ) of the normal adult brain. These findings were confirmed by conditional depletion of DCX-positive cells in transgenic mice carrying herpes simplex virus thymidine kinase (HSV-TK) under the control of the DCX promoter. In addition, the activated form of Notch1 (Notch intracellular domain, NICD) and its downstream transcriptional targets, Hes1 and sonic hedgehog (Shh), were also expressed in SVZ cells. Increased activation of Notch1 signaling increased SVZ cell proliferation, whereas inhibiting Notch1 signaling resulted in a reduction of proliferating cells in the SVZ. Levels of NICD, Hes1, and Shh were increased in the SVZ at 4 and 24 h after focal cerebral ischemia. Finally, ischemia-induced cell proliferation in the SVZ was blocked by inhibition of the Notch1 signaling pathway, suggesting that Notch1 signaling may have a key role in normal adult and ischemia-induced neurogenesis. Journal of Cerebral Blood Flow & Metabolism (2009) 29, 1644-1654; doi:10.1038/jcbfm.2009.83; published online 17 June 2009
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